Rapamycin attenuates the severity of murine adriamycin nephropathy.
BACKGROUND
Rapamycin is an immunosuppressive drug with potent antifibrotic activity. We evaluated the effect of rapamycin on murine adriamycin nephropathy, a model of progressive glomerulosclerosis and tubulointerstitial fibrosis.


METHODS
Adriamycin nephropathy was induced in Balb/c mice by a single intravenous injection of adriamycin. The mice were treated orally with either saline or rapamycin, beginning at the time of adriamycin injection or rapamycin starting 1 week after adriamycin injection. The mice were sacrificed 6 weeks after adriamycin injection.


RESULTS
Saline-treated mice developed massive proteinuria and impaired renal function. Kidney sections from saline-treated mice showed marked focal segmental glomerulosclerosis, tubular dilation with protein cast deposition, interstitial fibrosis, and numerous infiltrating macrophages and T lymphocytes. The intrarenal expression of Collagen I and RANTES was also increased. In contrast, both groups of rapamycin-treated mice had markedly reduced proteinuria and preserved renal function, with only mild histological abnormalities. The intrarenal expression of Collagen I and RANTES was reduced, concomitant with a significant reduction in interstitial inflammatory cell infiltration.


CONCLUSIONS
Rapamycin is effective in attenuating the glomerular and tubulointerstitial abnormalities in adriamycin nephropathy. The beneficial effects of rapamycin are mediated, at least in part, through reduced RANTES expression and inflammatory cell infiltration.
Lui
Sing Leung
SL
Dr. Lee Iu Cheung Memorial Renal Research Center, Tung Wah Hospital, Hong Kong SAR, China.
Tsang
Ryan
R
Chan
Kwok Wah
KW
Zhang
Florence
F
Tam
Sidney
S
Yung
Susan
S
Chan
Tak Mao
TM
D000419:Albuminuria / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001835:Body Weight; D018946:Chemokine CCL5 / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012720:Severity of Illness Index; D020123:Sirolimus / Q000494:pharmacology*; D015996:Survival Rate
D000903:Antibiotics, Antineoplastic; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D024042:Collagen Type I; D007166:Immunosuppressive Agents; D004317:Doxorubicin; D020123:Sirolimus